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Microreactors as the Key to the

Chemistry Laboratory of the Future

Karolin Geyer and Peter H. Seeberger*,1

Laboratory of Organic Chemistry,Swiss Federal Institute of Technology (ETH) ZurichWolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland

E-Mail: *[email protected]

Received: 4th September 2008 / Published: 16th March 2009

Abstract

The aim of synthetic chemists and the chemical industry is to perform

chemical transformations in a highly efficient and environmentally

benign manner. This involves atom economy and atom efficiency of

the particular reactions on one hand; on the other hand it includes

aspects of the reaction performance such as process safety, solvent

and reagent consumption, and purification procedures. A well-engi-

neered approach to elegantly overcome some of the aspects related to

process performance is the use of continuous-flow microfluidic devices

in chemical laboratories. This chapter highlights some application of

these new tools in synthetic laboratories and how continuous-flow

reactors may change the way chemists will perform their research in

the future.

Introduction

Research chemists typically perform chemical transformations in traditional glass round

bottomed flasks. Since the optimization of chemical transformations in batch reactors often

consumes substantial amounts of starting materials, a lot of precious building blocks as well

as effort and time are required in order to identify the ideal reaction conditions for a

87

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Systems Chemistry, May 26th – 30th, 2008, Bozen, Italy

1 New adress: Max-Planck-Institute of Colloids and Interfaces, Department of Biomolecular Systems,Am Muhlenberg 1, 14476 Potsdam-Golm, Germany; E-Mail: [email protected]

particular reaction. Having found the optimal conditions to achieve a certain reaction on a

small scale, process scale-up often poses additional challenges and requires further

adjustment of the reaction parameters. To overcome these hurdles in synthetic chemistry,

microstructured continuous-flow reactors and chip-based microreactors are becoming in-

creasingly popular [1].

Microstructured continuous-flow devices consist of a miniaturized channel system etched

into or established on materials such as metals, silicon, glass, ceramics or polymers, which

allows the chemical reaction to take place in a relatively narrow pore. These reaction

systems have a high interfacial area per volume (only depending on the radius of the

channel) and chemical reactions therefore profit from rapid heat and mass transfer. Due to

the high heat and mass transfer rates, the reaction time, yield and selectivity are strongly

influenced, often rendering processes to be more efficient and selective and thereby avoiding

the generally required purification processes. Besides the facile control of the physical

parameters, microreactors allow for low operational volumes to minimize reagent consump-

tion, the integration of on-line detection modules and an excellent process safety profile in

case highly exothermic reactions are undertaken, enhanced by the fact that only small

amounts of hazardous/explosive intermediates may be formed at any given time. To obtain

synthetically useful amounts of product, the reactors are simply run longer (‘‘scale-out’’

principle [1e]) or several reactors are placed in parallel (‘‘numbering up’’), assuring identical

conditions for the analytical and preparative modes. Many different applications of micro-

structured devices in synthetic chemistry have been reported and reviewed; [2, 3] here some

concepts and recent developments from our laboratory will be presented.

Microfluidic Reactor Types

Microreactors consist of a network of miniaturized channels often embedded in a flat sur-

face, referred to as the ‘‘chip’’ [1a]. Since different chemical applications call for different

types of reactors and materials, a variety of different possibilities have been explored.

Additionally, the size of microfluidic devices strongly influences their application and the

way in which reagents are introduced to the system [4]. The features of several selected

microreactors are summarized in Figure 1 [5].

Most commonly, glass, stainless steel, silicon or polymers (e. g. poly(dimethylsiloxane),

PDMS or poly(tetrafluoroethylene), PTFE) are used. Devices fabricated of PDMS are tra-

ditionally employed in biological and biochemical applications, [11] whereas stainless steel

based microreactors are mostly applied in meso-scale production efforts [2b, 12]. Glass

devices allow for the visual inspection of the reaction progress [13] or for application to

photochemical reactions, [14] whereas silicon reactors offer excellent heat transfer rates due

to the high thermal conductivity of silicon and therefore often are the reactors of choice due

to their well established fabrication procedures [2 d, 3b–e, 15].

88

Geyer, K. and Seeberger, P.H.

Figure 1. Selected microreactors; Top row from left to right: Silicon-based micro-

reactor designed by Jensen [3b, 10]; Glass microreactor by Syrris� [6]; Stainless steel

microreactor system by Ehrfeld Mikrotechnik� [7]. Bottom row from left to right:

Glass microreactor by Haswell [1b, 1 l]; Stainless steel microreactor of the CYTOS�

Lab system[8]; Glass microreactor by Micronit Microfluidics�[9]; Large picture right:

Vapourtec� tube reactor [10].

The initial investigations of our group employed a stainless steel microreactor system

designed by Ehrfeld Mikrotechnik [3a, 7] (see Figure 1). We further focused on the applica-

tion of silicon-glass microreactors [3b-e, 15] as the glass layer would offer the possibility to

visually inspect the reaction and the silicon portion would provide a rapid heat transfer.

Further investigations were carried out in commercially available glass and PTFE tube

microreactors [3f-h, 6], and other system are currently under evaluation or being developed.

Synthesis in Microchemical Systems

Due to the small channel dimensions and the increased surface to volume ratio of micro-

reactors, mass and heat transport are significantly more efficient than in the classic round-

bottomed flask. The mixing of reagents by diffusion occurs very quickly, and heat exchange

between the reaction medium and reaction vessel is highly efficient. As a result, the reaction

conditions in a continuous-flow microchannel are homogenous, and can be controlled pre-

cisely. Therefore, highly exothermic and even explosive reactions can be readily harnessed

in a microreactor. The careful control of reaction temperature and residence time has a

beneficial effect on the outcome of a reaction with respect to yield, purity and selectivity.

Below, selected examples from our laboratory are described to illustrate the potential appli-

cation of microreactors to organic synthesis. The application of microreactors to small-scale

medicinal and academic total synthesis is just beginning.

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Microreactors as the Key to the Chemistry Laboratory of the Future

Chemical Reactions: Initial Investigations and Synthesis

of Biopolymers

Liquid-phase reactions performed in micro structured devices benefit particularly from the

efficient mass and heat transport characteristics of microreactors and the small amounts of

reactants (e. g. hazardous reagent or intermediates, precious starting materials) being present

in the system at any given time.

Our laboratory initially explored the relevance of microreactor technology in synthetic

chemistry employing a stainless steel microreactor system (see Figure 1, Scheme 1) [3a].

The system was used to undertake various important synthetic transformations such as

Williamson ether synthesis (eq. 1), Diels-Alder reactions (eq. 2), Horner-Wadsworth-Em-

mons reactions (eq. 3) and Henry reactions (eq. 4). Since a significant number of chemical

transformations require solid catalysts to proceed in a reasonable reaction time and selectiv-

ity, investigations were undertaken to perform reactions of a heterogeneous nature in con-

tinuous-flow. A pre-packed reaction cartridge, loaded with an active catalyst on polymer

beads, was placed in the continuous-flow system to allow palladium mediated cross-cou-

pling reactions (Heck reaction, eq. 5) to take place [3a].

Scheme 1. Selected transformations carried out in a stainless steel microreactor system

(y = yield) [3a].

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The chemical synthesis of carbohydrate building blocks or small oligosaccharides remains a

challenging task for synthetic chemists since a huge variety of components influence the

outcome of a given glycosylation [3b, d]. The chemical outcome of such transformations

depends strongly on the steric and electronic properties of the coupling partners, reagent

concentrations, reaction temperature and reaction time. Furthermore, the building blocks

used for oligosaccharide assembly often require multistep syntheses and are precious syn-

thetic intermediates themselves. A silicon-glass microreactor, allowing for careful control of

the reaction parameters, was employed to investigate glycosylations in continuous-flow

(Scheme 2) [3b]. The small internal volume of 78mL minimized reagent and building block

consumption. The reaction progress of the coupling between protected mannoside 14 and

galactoside 15 was monitored as a function of time and temperature (Fig. 2).

Scheme 2. Initial application of the silicon-glass microreactor to carbohydrate chem-

istry [3b].

It was revealed that at low temperatures (�80 �C to �70 �C) and short reaction times

(< 1 min) the formation of orthoester 17 was favored, whereas higher temperatures

(�40 �C) and longer reaction times (~ 4 min) led to formation of the desired a-linked product

16. Using as little as 100 mg of starting materials, 40 different reaction conditions were

scanned within one day [3b].

91


Figure 2. Starting material consumption and product formation of a glycosylation

reaction [3b].

Having proven the applicability of the silicon-glass microreactor in carbohydrate chemistry,

we were interested in investigating the influence of reaction temperature, reagent concentra-

tion, solvent and anomeric leaving group on the selective outcome of a given glycosylation.

Therefore comparative studies employing mannosyl building blocks 14, 19 and 20 respec-

tively were undertaken to screen for the optimal reaction conditions varying reaction time,

temperature, solvent and reagent concentration (Scheme 3) [3 d].

92


Scheme 3. Comparative studies of glycosylation reactions using varying glycosylating

agents and solvent system [3 d].

Figure 3. Product distribution at the optimal reaction conditions found by screening;

Left side: Glycosylations employing reactant 14; Right side: Glycosylations employ-

ing reactant 20; Table: Scale-out of the optimized procedures [3 d].

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It was discovered that glycosylations in toluene as the solvent proceeded more selectively

than in dichloromethane (Fig. 3). While in dichloromethane even at optimized reaction

conditions undesired b-disaccharide 22 and orthoester 23 are formed, a-disaccharide 21 is

exclusively formed in toluene. Scale-up of the established synthetic procedures yielded the

desired saccharide 21 in good to excellent yields (81% and 93% respectively) in short

reaction times (2 min, 8 min) [3 d].

After having established the reaction conditions for single glycosylation reactions in silicon-

glass microreactors, the synthesis of an oligosaccharide in continuous-flow was explored

[3e]. Glycosylphosphate 24 was iteratively coupled to a growing carbohydrate chain on a

perfluorinated support linker for facile purification by fluorous solid phase extraction (FSPE

[17]) to deliver the desired oligosaccharides (Scheme 4). In-situ deprotection of the primary

alcohol of each carbohydrate allowed for a reaction sequence of coupling and deprotection

within reaction times of up to one minute per sequence to obtain the desired oligosaccharide

in excellent yield (Scheme 5). The perfluorinated support linker of homotetrasaccharide 29

could, after successful assembly of the structure, be further functionalized to yield terminal

olefins, aldehydes and trichloroacetimidates allowing for further synthetic transformations

and attachment onto slides for biological investigations respectively (Scheme 6) [3e].

Scheme 4. Synthesis of the glucose based homotetramer 29 via iterative

glycosylation [3 e].

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Scheme 5. Scale-out of the established coupling procedures [3e].

Scheme 6. Functionalization of the perfluorinated linker after successful assembly of

the homotetramer 29 [3e].

b-Amino acid oligomers (b-peptides) present a unique class of peptides. In contrast to their

natural a-amino acid derived counterparts, b-peptides show remarkable metabolic stability

and are therefore of increasing interest for the pharmaceutical industry and the treatment of

various diseases. Nevertheless, b-peptides require relatively few residues to form secondary

structures like turns, helices or sheets [18], which usually leads to a lack of solubility in

commonly employed solvents. Therefore, the synthesis of b-peptide structures is severely

hampered [19]. Usually, high coupling temperatures are applied to circumvent precipitation

of the peptides during the reaction, but the problem of low solubility remains unsolved for

the required purification steps.

95


We investigated the application of a silicon-glass microfluidic reactor to the assembly of

oligo-b-peptides (Scheme 7) [3c]. The microfluidic device thereby not only allowed for

quick screening of reaction conditions and the controlled heating of the reaction mixture

to unconventionally high temperatures, but also the procurement of synthetically useful

amounts of peptides. The attachment of a perfluorinated linker again allowed for facile

purification of the reaction mixtures by FSPE [17] to yield the desired oligopeptides 35,

37 and 39 in excellent yields and short reaction times. Notably, the high reaction tempera-

tures of up to 120 �C did not affect deprotection of the tert-butyloxycarbonyl (Boc) protected

peptides, and highly reactive b2-and b3-homoaminoacid fluorides were employed for the b-peptide couplings. Furthermore, all possible b-peptide linkages were successfully installed,

even the sterically most demanding b3-b2 linkage. Including global deprotection and clea-

vage from the perfluorinated linker the microreactor approach significantly increased the

isolated overall yield of desired tetrapeptide 39 compared to solid phase or solution phase

approaches (Scheme 7) [3c].

Scheme 7. Synthesis of a b-tetrapeptide in continuous-flow [3c].

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Chemical Reactions: Evaluation of Microreactors for

Hazardous Chemical Transformations and Scale-Up

More recently, we explored the applicability of microreactor technology for hazardous

synthetic transformations that are unattractive, difficult or even impossible to be performed

using batch procedures, especially on large scale. With the aim to speed up the transfer from

development stage to production scales in chemical companies for synthetically useful

transformations, we investigated reactions such as AlMe3 mediated amide bond formations

[3f], deoxyfluorinations using diethylaminosulfur trifluoride (DAST) [3 g], radical defunc-

tionalisations and hydrosilylations in commercially available glass and tube microreactors

(Fig. 4) [3 h, 6].

Figure 4. Microreactor based approaches toward hazardous reactions and scale-up

chemistry [3f, g, h].

Amide bond formations are frequently used transformations in chemistry laboratories and

generally require, starting from esters, a three step procedure including hydrolysis, activation

and treatment with an amine to be synthesized (Scheme 8). Aluminium-mediated amide

bond formations resembling direct Weinreb-amidation methods are, even though the reaction

conditions render the transformation highly tolerant towards further functional groups in the

molecule, less commonly applied due to the difficulties in safe handling of trimethylalumi-

nium (AlMe3). In addition, the aluminium-amide intermediates are unstable at elevated

temperatures and are known to result in severe exotherms at room temperature. We inves-

tigated the applicability of microreactor technology for aluminium-mediated amide bond

formation to develop a general protocol for the safe and rapid production of useful amounts

of material (1 – 2 mol/day). A huge variety of primary and secondary amines as well as

carboxylic acids derivatives were transformed into their corresponding amides in just two

minutes reaction time (Scheme 9). Notably, installing a simple backpressure regulator

97


allowed for superheating of the solvents while still allowing for the reaction to proceed

chemoselectively (amide 60) and to tolerate functional groups such as carbon-carbon double

bonds (54, 56), hydroxyl groups (55, 57) or carbocycles (58, 59).

Scheme 8. General pathway for the formation of amides [3f].

Scheme 9. Selected examples for AlMe3 mediated direct amide bond formation [3f].

The developed general synthetic protocol was further applied to the continuous synthesis of

Rimonabant� (Scheme 10) [3f]. Rimonabant� is an anti-obesity drug by Sanofi-Aventis� that

acts as a central cannabinoid receptor antagonist and is approved in Europe [20]. The entire

synthesis was performed in continuous-flow, starting from aromatic ketone 62 and

98


diethyloxalate 63 to form diketone 64 in 70% over 10 min. Formation of pyrazole 66 was

established in AcOH at 125 �C and a reaction time of 15 min. As the last synthetic trans-

formation, the AlMe3 mediated amide bond formation was performed to yield Rimonabant�

68 in an overall yield of 49% (Scheme 10) [3f].

Scheme 10. Synthesis of Rimonabant� 68 in continuous-flow with AlMe3 mediated

amide bond formation as the key step [3f].

Fluorinated biologically active organic compounds are of great interest in pharmaceutical

industry due to their unique biochemical and physical properties. Besides the generation of

fluorinated molecules by nucleophilic substitutions starting from halides and HF or KF [21],

or electrophilic fluorinations of b-diketones via an enole pathway [22], deoxyfluorinations

using deoxofluor or DAST are convenient reaction pathways due to the ready availability of

unprotected hydroxyl functionalities in organic molecules [3 g, 23]. Nevertheless, the synth-

esis of fluorinated drug candidates, their precursors or organic molecules in general via

deoxyfluorinations is severely hampered due to safety concerns. The most commonly used

reagent DAST detonates at 90 �C, forms HF after contact with moisture or water which

makes the use of special equipment necessary and is ideally avoided on large scale. We were

interested in investigating DAST mediated deoxyfluorinations of alcohols, aldehydes, lactols

and carboxylic acids in a continuous-flow PTFE tube reactor. Installation of a backpressure

regulator allowed for superheating of THF close to the detonation point of DAST, and an in-

situ quench with aqueous NaHCO3 immediately destroyed remaining DAST or formed HF

(Fig. 5) [3 g].

99


Figure 5. Overview of the DAST mediated deoxyfluorinations in continuous-

flow [3 g].

Various primary and secondary alcohols underwent transformation into the corresponding

fluorinated building block in high yields (Scheme 11). Consistent with the overall effort of

our group to facilitate oligosaccharide assembly, electron rich and electron deficient glucosyl

fluorides 74 and 75 were rapidly obtained in high yields from the corresponding lactols and

did not require further purification before being used as glycosylating agents.

Scheme 11. Deoxyfluorinations of various alcohols and lactols [3 g].

100


In a further attempt to rapidly generate reactive intermediates, aromatic and aliphatic car-

boxylic acids were transformed into their corresponding acid fluorides (Scheme 12). Parti-

cularly impressive is the selective formation of the acid fluorides in case enolizable a-protons are present (78, 79, 80), no a-fluorination was observed. Furthermore, acid chloride

81 was selectively converted into the corresponding acid fluoride.

Scheme 12. Deoxyfluorinations of carboxylic acids and acid fluorides [3 g].

To generate difluoromethylene moieties, electron rich, electron deficient and sterically de-

manding aromatic aldehydes as well as aliphatic aldehydes underwent deoxyfluorination to

yield the analogous fluorinated derivative in high yields (Scheme 13). Remarkably, ketone

87 as a sterically and electronically more challenging substrate, was transformed into the

corresponding difluoromethylene derivative in 40% yield [3 g, 24].

101


Scheme 13. Synthesis of difluoromethylene moieties via DAST mediated deoxyfluor-

inations [3 g].

The latest investigations in our laboratories explored free radical mediated reactions such as

dehalogenations, Barton-McCombie type deoxygenations and hydrosilylations in continu-

ous-flow (Fig. 6) [3 h].

Figure 6. Free radical based transformations performed in glass microreactors [3 h].

Deoxygenations and dehalogenations are important synthetic transformations since they are

highly versatile reactions and tolerate a huge variety of further functional groups in the

molecules. Unfortunately, the concentration of free radicals in the reaction mixture often

influences the selective outcome of the reaction strongly. Careful control of the reaction

temperature is required to circumvent thermal runaways. Investigating reactions in a con-

tinuous-flow glass microreactor using tris(trimethylsilyl)silane (TTMSS) as a non-toxic

variant of the generally applied tin reagent Bu3SnH resulted in high yielding dehalogena-

tions and deoxygenations at a reaction temperature of 130 �C (superheated toluene,

102


established by a backpressure regulator) and a reaction time of five minutes (Scheme 14).

Notably, taking advantage of the controlled reaction performance in the microreactor, the

xanthate moiety of the difunctionalized dodecane 96 was removed chemoselectively [3 h].

Scheme 14. Radical mediated dehalogenations and deoxygenations in continuous-

flow [3 h].

Hydrosilylations, the addition of Si-H bonds across unsaturated carbon-carbon bonds, are

the most important synthetic transformation for the generation of organosilicon compounds.

Especially tris(trimethylsilyl)silane TTMSS adds highly regioselectively to various alkynes

via a free-radical chain mechanism to form vinyl silanes [25]. We envisaged that the rapid

heat transfer in microreactors would effect the E/Z selectivity of the resulting silanes while

significantly reducing the reaction time (Scheme 15).

Scheme 15. Hydrosilylations of alkynes performed in a glass microreactor [3 h].

103


Again applying reaction conditions of 130 �C in toluene and a reaction time of five minutes

yielded the desired anti-Markovnikov products in excellent yields and good stereo-selectiv-

ities. The microreactor approach further furnished the hydrosilylation product of phenylace-

tylene 97 in greater yield (96% vs. 88%) and superior Z/E ratio (98:2 vs. 84:16) compared to

traditional batch strategies [3 h, 25].

Conclusion

Many chemical transformations can be performed in a faster, safer and cleaner manner when

performed in microfluidic devices. The down-scaling of reaction volumes in microreactors

offers the more precise control of the reaction conditions (temperature, time, mixing) and the

use of minimal amounts of precious compounds to rapidly screen a variety of conditions,

generating a wealth of information on reaction kinetics and pathways. Additionally, micro-

reactors present the opportunity to apply reaction conditions that are inaccessible using

conventional laboratory equipment, such as super heated solvents, and safely performing

reactions in explosive regimes. Even though numerous impressive examples on the applica-

tion of microreactor technology in synthetic chemistry have been reported, some major

drawbacks associated with this technique remain: the incompatibility of reactors with solid

reagents that cannot be used for wall-coatings or be supported on linkers, the sensitivity to

precipitations and the useful applicability mainly to fast reactions. Additionally, the efficient

on-line analysis of reaction mixtures in a high throughput format represents an outstanding

issue. The overall concept of highly efficient continuous-flow microreactor techniques re-

quires further improvements before it will be applied as a standard tool in chemical labora-

tories.

References

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[4] Reagent introduction and feed can occur via electroosmotic flow, hydrodynamic

pumping (HPLC pumps, syringe pumps) or capillary flow.

[5] A wide variety of other microreactors is available from other manufacturers and

suppliers, e. g.: Institute for Microtechnology Mainz (IMM), Fraunhofer Alliance

for Modular Microreaction Systems (FAMOS), the Little Things Factory (LTF) in

Ilmenau, the New Jersey Centre for MicroChemical Systems (NJCMCS), the Micro-

Chemical Process Technology Research Association (MCPT), or Sigma-Aldrich. The

selection presented here is by no means exhaustive and only serves to indicate the

diversity in systems developed to date.

[6] For further information visit the webpage: http://www.syrris.com/.

[7] For further information visit the webpage: http://www.ehrfeld.com.

[8] For further information visit the webpage: http://www.cpc-net.com/cytosls.shtml.

[9] For further information visit the webpage: http://www.micronit.com/

[10] For further information visit the webpage: http://www.vapourtec.co.uk/

105


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Nojima, T., Shinohara, Y., Baba, Y., Fujii, T. (2008) Anal. Sci. 24:234.

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(a) Taghavi-Moghadam, S., Kleemann, A., Golbig, K.G. (2001) Org. Process Res.

Dev., 5:652. (b) Panke, G., Schwalbe, T., Stirner, W., Taghavi-Moghadam, S., Wille,

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Dev. 10:417. (f) Wheeler, R.C., Benali, O., Deal, M., Farrant, E., MacDonald, S.J.F.,

Warrington, B.H. (2007) Org. Process Res. Dev. 11:704.

[13] For reports on the application of glass microreactors see: (a) Nikbin, N., Watts, P.

(2004) Org. Process Res. Dev 8:942. (b) Wiles, C., Watts, P., Haswell, S.J. (2007)

Chem. Commun. 9:966. (c) Wiles, C., Watts, P., Haswell, S.J. (2007) Lab Chip 7:322.

(d) Hornung C.H., Mackley, M.R., Baxendale, I.R., Ley, S.V. (2007) Org. Process

Res. Dev. 11:399. (e) Smith, C.D., Baxendale, I.R., Tranmer, G.K., Baumann, M.,

Smith, S.C., Lewthwaite, R.A., Ley, S.V. (2007) Org. Biomol. Chem. 10:1562.

(f) Smith, C.D., Baxendale, I.R., Lanners, S., Hayward, J.J., Smith, S.C., Ley, S.V.

(2007) Org. Biomol. Chem. 10:1559.

[14] For recent reviews and reports on photochemical reactions using microflow see

(a) Fukuyama, T., Hino, Y., Kamata, N., Ryu, I. (2004) Chem. Lett. 33:1430.

(b) Maeda, H., Mukae, H., Mizuno, K. (2005) Chem. Lett. 34:66. (c) Maeda, H.,

Matsukawa, N., Shirai, K., Mizuno, K. (2005) Tetrahedron Lett. 46:3057. (d) Hook,

B.D.A., Dohle, W., Hirst, P.R., Pickworth, M., Berry, M.B., Booker-Milburn, L.I.

(2005) J. Org. Chem. 70:7558. (e) Matsushita, Y., Kumada, S., Wakabayashi, K.,

Sakeda, K., Ichimura, T. (2006) Chem. Lett. 35:410. (f) Lainchbury, M.D., Medley,

M.I., Taylor, P.M., Hirst, P., Dohle, W., Booker-Milburn, L.I. (2008) J. Org. Chem.

DOI: 10.1021/jo801108 h.

[15] For selected reviews and reports on silicon based microreactors see (a) Jensen, K.F.

(2001) Chem. Eng. Sci. 56:293. (b) Yen, B.K.H., Gunther, A., Schmidt, M.A.,

Jensen, K.F., Bawendi, M.G. (2005) Angew. Chem. Int. Ed. 44:5447. (c) Murphy, E.R.,

106


Martinelli, J.R., Zaborenko, N., Buchwald, S.L., Jensen, K.F. (2007) Angew. Chem.

Int. Ed. 46:1734. (d) Kralj, J.G., Sahoo, H.R., Jensen, K.F. (2007) Lab Chip 7:256.

(e) Inoue, T., Schmidt, M.A., Jensen, K.F. (2007) Ind. Eng. Chem. Res. 46:1153.

[16] (a) Ravida, A., Liu, X.Y., Kovacs, L., Seeberger, P.H. (2006) Org. Lett. 8:1815.

(b) Liu, X.Y., Stocker, B.L., Seeberger, P.H. (2006) J. Am. Chem. Soc. 128:3638.

[17] (a) Curran, D.P. (2001) Synlett. 9:1488. (b) Curran, D.P., Luo, Z.Y. (1999) J. Am.

Chem. Soc. 121:9069. (c) Zhang, W. (2004) Chem. Rev. 104:2531.

[18] (a) Murray, J.K., Gellman, S.H. (2005) Org. Lett. 7:1517. (b) Lelais, G., Seebach, D.,

Jaun, B., Mathad, R.I., Flogel, O., Rossi, F., Campo, M., Wortmann, A. (2006) Helv.

Chim. Acta 89:361.

[19] Erdelyi, M., Gogoll, A. (2002) Synthesis 1592 – 1596.

[20] Monnier, O., Coquerel, G., Fours, B., Duplaa, H., Ochsenbein, P., PTC Patent, PCT/

FR2007/000201, 05.02.2007.

[21] For selected examples on nucleophilic substitutions using HF or fluorine salts, see

(a) Kim, D.W., Song, C.E., Chi, D.Y. (2003) J. Org. Chem. 68:4281. (b) Inagaki, T.,

Fukuhara, T., Hara, S. (2003) Synthesis 1157.

[22] For electrophilic fluorinations see for example Xiao, J., Shreeve, J.M. (2005)

J. Fluorine Chem. 126:473.

[23] For selected examples on fluorinations using DAST or deoxofluor see (a) Lal, G.S.,

Pez, G.P., Pesaresi, R.J., Prozonic, F.M., Cheng, H. (1999) J. Org. Chem. 64:7048.

(b) White, J.M., Tunoori, A.R., Turunen, B.J., Georg, G.I. (2004) J. Org. Chem.

69:2573.

[24] These finding are consistent with the literature, see also Negi, D.S., Koppling, L.,

Lovis, K., Abdallah, R., Geisler, J., Budde, U. (2008) Org. Process Res. Dev. 12:345.

[25] Kopping, B., Chatgilialoglu, C., Zehnder, M., Giese, B. (1992) J. Org. Chem.

57:3994.

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